1. Field of the Invention
The invention relates to a gene which is affected significantly by tumour-specific deletions in human neuroblastomas and is involved in tumour genesis.
2. Description of Related Art
A group of proteins which have been shown to act predominantly as activators of transcription share common motifs for dimerisation and DNA binding (Jones, 1990). The dimerisation domain is an amphipathic Helix-Loop-Helix (HLH)-region, and the DNA-binding is made easier by a section of basic amino acids which precede the HLH domain (Murre et al., 1989a,b). Proteins which contain this basic Helix-bop-Helix pattern (bHLH) may form homo- and heterodimers. The modulation of the transcriptional activation by bHLH factors is brought about by another group of dimerising proteins. This was established in the course of identifying the Id protein, a protein which also contains a Helix-Loop-Helix pattern but which lacks the basic region (HLH proteins) (Benezra et a., 1990). Id forms heterodimers with some members of the family of the bHLH transcription factors. Since it lacks the basic region which is responsible for DNA binding, heterodimers which contain Id cannot bind DNA. Therefore, bHLH proteins are most probably regulated negatively by HLH proteins such as Id. Other examples of regulatory bHLH and HLH protein interactions are the genes of the Drosophila achaete-scute-complex and the extramacrochaetae (emc) gene (Ellis et al., 1990; Garell and Modolell, 1990). These genes have a function in developing the sense organs of the peripheral nervous system (Ghysen and Dambly-Chaudiere, 1989). In general, genes which code for Helix-Loop-Helix proteins are presumed to be involved in controlling cell differentiation.
Cell differentiation is one of the processes which is affected by neoplastic transformation. Therefore, the function of genes involved in the these processes must be disrupted in tumour cells. The appearance of both dominant and recessive mutations in tumours must reflect the normal function of the affected genes as either positive or negative regulators. Up till now, Helix-Loop-Helix proteins have only been found to have effects based on dominant mutations, eg. the oncogenic activation of myc genes (Luscher and Eisenmann, 1990; Zimmerman and Alt, 1990). However, in view of the different functions of the genes coding for HLH proteins it could also be borne in mind that genes of this type are affected by recessive mutations and therefore have properties which correspond to the tumour suppressor genes.
Allelic deletions in specific regions of the genome, which occur significantly frequently in tumour genomes, are used as marking points for the position of tumour suppressor genes (Weinberg, 1991). In investigations of human neuroblastomas a consensus deletion was defined in chromosome lp36.2-p36.1 (Weith et al., 1989). The allelic loss of this section in about 80-90% of the tumours investigated led to the supposition that a gene which prevents tumours is located in this region.